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S. Visser
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Optimizing targeted therapy in lung cancer (ID 56)
- Event: ELCC 2018
- Type: Poster Discussion session
- Track:
- Presentations: 1
- Moderators:F. Cappuzzo, N. Peled
- Coordinates: 4/12/2018, 16:45 - 17:45, Room W
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132PD - Plasma concentrations of pemetrexed to predict clinical outcomes in patients with advanced NSCLC (ID 614)
16:45 - 17:45 | Presenting Author(s): S. Visser
- Abstract
Background:
Currently, there are no clinically useful predictors of efficacy and toxicity to pemetrexed (PMX) in advanced non-small-cell lung cancer (NSCLC). Using population pharmacokinetic (pop-PK) modelling, we explored whether total exposure to PMX predicts for progression-free and overall survival (PFS/OS) and occurrence of (severe) chemotherapy (CTx)-related adverse events (AEs).
Methods:
In a prospective observational multi-center study, patients with stage IIIB/IV NSCLC receiving first- or second-line PMX(/platinum) were enrolled. PMX (500 mg/m[2]) was administered as a 10-min intravenous infusion every 21 days. Prior to and weekly after each PMX administration, plasma sampling was performed (cycle PK). In a subgroup, blood samples were also collected at 10, 30 minutes and 1, 2, 4, 8, 24 hours after start of PMX infusion (24h PK). With pop-PK modelling total exposure (AUC) to PMX per patient was estimated. The relation between AUC during cycle 1 (AUC~1~) and OS/PFS in treatment-naïve patients was examined using Cox regression analyses and in all patients we compared the difference in mean AUC~1~ between patients with and without grade ≥3 CTx-related AEs (CTCAE 4.03) during total treatment of 4 cycles.
Results:
For 106 of the 165 patients, concentrations of PMX were quantified (24h PK, n = 15; cycle PK, n = 106). Median estimated AUC~1~ was 201 mg·h/L (interquartile range: 179–224). In treatment-naive patients (n = 95), AUC~1~ did neither univariably predict for OS/PFS, nor multivariably when adjusted for prognostic factors sex, disease stage and WHO performance score (OS, HR = 1.05, 95%CI: 1.00–1.11; PFS, HR = 1.03, 95%CI:0.98–1.08). Compared to patients without ≥ grade 3 CTx-related AEs (n = 51), patients with ≥ grade 3 CTx-related AEs (n = 55) had significantly higher AUC~1~ values (220 vs 191, p < 0.001). When seperating ≥ grade 3 CTx-related AEs into clinical and laboratory AEs, identical results were found.
Conclusions:
Total systemic exposure to PMX does not predict for PFS/OS, but is significantly associated with more frequent occurrence of severe CTx-related AEs. Although the impact of peak concentrations on efficacy remains unclear, our findings suggest that lower dosage might prevent severe toxicity with preservation of efficacy.
Clinical trial identification:
Legal entity responsible for the study:
Erasmus MC
Funding:
ZonMw
Disclosure:
J. Aerts: Member of Scientific Committee ELCC 2018; consultant/advisory role with Eli Lilly and Company. All other authors have declared no conflicts of interest.
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Poster Display session (Friday) (ID 65)
- Event: ELCC 2018
- Type: Poster Display session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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168P - Pemetrexed dosing regimens in patients with advanced NSCLC (ID 617)
12:30 - 13:00 | Presenting Author(s): S. Visser
- Abstract
Background:
There is a lack of rationale to use body surface area (BSA)-based dosing if BSA is not a predictor of systemic clearance and thus total systemic exposure (AUC). Using population pharmacokinetic (Pop-PK) modelling, we evaluated the influence of BSA and renal function on pemetrexed (PMX) clearance and compared different dosing strategies.
Methods:
In a prospective observational multi-center study, patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) receiving PMX(/platinum) first- or second-line were enrolled. PMX (500 mg/m[2]) was administered as a 10-min intravenous infusion every 21 days. Prior to and weekly after each PMX administration, plasma sampling was performed (cycle-PK) and glomerular filtration rate (eGFR) was estimated. In a subgroup, sampling was also performed at 10,30 minutes and 1,2,4 and 8 hours after start of PMX infusion (24h PK). With the ultimate Pop-PK model, we simulated different dosing strategies and compared differences in median AUC (interquartile range [IQR]) and interindividual variability (coefficient of variation [CV]) of AUC to standard BSA-based dosing.
Results:
For 106 of the 165 patients, concentrations of PMX were quantified (24h PK, n = 15; cycle PK, n = 106). A two-compartment model (population estimate (%standard error of the estimate) in terms of PMX clearance (CL; 4.58L/h (3.1%)), central distribution volume (V~1~; 15.9L (3.3%)), peripheral distribution volume (V~2~; 21.6L (5.0%)), intercompartimental clearance (Q; 0.05L/h (4.7%)) and between-patient variability of CL (16.7%), fitted PK data appropriately. Covariate eGFR significantly reduced between-patient variability in CL from 20.2% to 16.7% (p < 0.005), while BSA did not. Compared to BSA-based dosing (CV 22.5%, AUC 206 (IQR 178–240)), simulation of eGFR-based dosing (CV 18.5%, AUC 206 (IQR 183–232)) and fixed dose of 900 mg with 25% dose reduction if eGFR < 60 (CV 19.1%, AUC 197 (174–224)) both showed less interindividual variability of AUC.
Conclusions:
Although we currently dose PMX based on BSA, our data show better rationale for eGFR-based dosing as it offers additional control of systemic exposure to PMX, indicated by the decreased variability. Using fixed dose of 900 mg with 25% dose reduction if eGFR < 60 may be an acceptable alternative in clinical practice.
Clinical trial identification:
Legal entity responsible for the study:
Erasmus MC
Funding:
ZonMw
Disclosure:
J. Aerts: Member of scientific committee ELCC 2018 consultant/advisory role with Eli Lilly and Company All other authors have declared no conflicts of interest.
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169P - Nephrotoxicity of pemetrexed maintenance in patients with advanced NSCLC: Two cohort studies (ID 534)
12:30 - 13:00 | Presenting Author(s): S. Visser
- Abstract
Background:
Optimal survival benefit from different lines of anticancer treatment in advanced non-small-cell lung cancer (NSCLC) requires conservation of renal function. We evaluated the development of renal impairment and its clinical significance during pemetrexed maintenance.
Methods:
In a prospective multi-center cohort study, patients with advanced (stage IIIB/IV) NSCLC treated with first-line (platinum-combined) or second-line pemetrexed were enrolled. After platinum-based induction patients were eligible for pemetrexed maintenance if no disease progression occurred. We evaluated the incidence of acute and chronic kidney disease (AKD/CKD), treatment discontinuation frequency due to renal impairment and associations of clinical variables with AKD during maintenance. Both AKD and CKD were defined in accordance with the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines. We validated findings in an independent cohort of advanced NSCLC patients treated with pemetrexed maintenance.
Results:
In total 213 patients received pemetrexed. In the primary cohort 165 patients started induction of whom 47 (28%) continued maintenance. During maintenance 16 patients (34%) developed AKD, leading to CKD in 11 (69%) and treatment discontinuation in 9 (56%) in the primary cohort. Lower eGFR (unit 5 mL/min/1.73 m[2]) before start of induction (OR 1.32, 95%CI: (1.06–1.64) and relative decline (per 10%) in eGFR during induction (OR 2.11, 95%CI: 1.22–3.65) were univariably associated with AKD during maintenance. In the independent cohort (n = 48), these similar associations could be demonstrated. In this cohort, 24 patients (50%) developed AKD, leading to CKD in 13 (54%) and treatment discontinuation in 7 (29%).
Conclusions:
Patients are at risk for renal impairment during pemetrexed maintenance, which may jeopardize further lines of anticancer treatment. Patients whose renal function is impaired before – or declines during – induction treatment are more vulnerable. Renal protective strategies for patients at increased risk might be beneficial, such as continuation of hydration during pemetrexed maintenance or dosing based on renal function.
Clinical trial identification:
Legal entity responsible for the study:
Erasmus MC
Funding:
ZonMw
Disclosure:
J. Aerts: Member of Scientific Committee ELCC; Consultant/advisory role with Eli Lilly and Company. All other authors have declared no conflicts of interest.
